Injectable and pH-Sensitive Hyaluronic Acid-Based Hydrogels with On-Demand Release of Antimicrobial Peptides for Infected Wound Healing

Antibiotics’ abuse in bacteria-infected wounds has threatened patients’ lives and burdened medical systems. Hence, antibiotic-free hydrogel-based biomaterials, which exhibit biostability, on-demand release of antibacterial agents, and long-lasting antimicrobial activity, are highly desired for the treatment of chronic bacteria-infected wounds. Herein, we developed a hyaluronic acid (HA)-based composite hydrogel, with an antimicrobial peptide [AMP, KK­(SLKL)₃KK] as a cross-linking agent through Schiff’s base formation, which exhibited an acidity-triggered release of AMP (pathological environment in bacteria-infected wounds, pH ∼ 5.5–5.6). During the self-assembly process, AMP adopted an antiparallel β-sheet secondary structure due to the alternate arrangement of hydrophobic and hydrophilic residues of amino acids. Owing to Schiff’s base formation between the primary amines derived from lysine residues and the aldehydes in oxidized HA, the AMP–HA composite hydrogel exhibited injectability, high biostability, and enhanced mechanical strength. Importantly, both AMP and the AMP–HA composite showed excellent broad-spectrum antibacterial activity in vitro and in vivo. Specifically, the AMP–HA composite hydrogel exhibited on-demand full thickness wound healing in an infected mice model. Therefore, this work provides an efficient strategy to fabricate antibiotic-free hydrogel-based biomaterials for the management of chronic bacteria-infected wounds.